A Brief History of Tofacitinib


In the summer of 1993, Dr. Paul Changelian, a scientist in Pfizer’s immune suppression group, was looking for a new way to prevent organ transplant rejection. Paul, always on the lookout for new ideas, particularly ones related to suppressing an overactive immune systems (a hallmark of diseases like psoriasis and rheumatoid arthritis as well as organ rejection) decided to attend the FASEB Summer Conference on Lymphocytes and Antibodies, a meeting held in Vermont where the world’s leading scientists got together to discuss cutting edge research. Actually, he almost didn’t attend the meeting. His wife, Diane, was expecting their second child and her due date was around the same time as the meeting. Paul was hesitant about being away, as he worried that Diane might go into early labor. But Diane knew that this conference was important to Paul, and so she suggested to that they both go up to Vermont, as their second child could be delivered just as easily in Vermont as in Connecticut. Thus, they both ventured north.

While at this meeting, Paul ran into an old acquaintance, Dr. John O’Shea, a researcher at the NIH. As scientists are wont to do, Paul and John discussed their current projects. When Paul told John that he was hunting for new drug targets that could produce immune suppression, John mentioned that his lab had just discovered a particular enzyme from a class known as kinases that could play a role in immune function. The enzyme is a member of the Janus family of kinases and is commonly known as JAK. JAK was shown to control signaling by interleukin-2, a key growth factor for T lymphocytes, the cells responsible for the rejection of a transplanted kidney.

Paul was intrigued by these findings, but he did have a concern. At that time, other laboratory data suggested that interleukin-2 was not the only growth factor used by T lymphocytes, and blocking it via the JAK pathway might not be sufficient to turn down an overactive immune system. The only way to get the answer to this key question was to start a discovery program to find a safe and effective JAK inhibitor and to then test it in patients.

Working closely with the NIH, Pfizer was able to sign the necessary agreements to enable the project to begin. But a totally novel project like this was essentially starting from scratch as all of the necessary assays and in vivo models needed to be developed. More importantly, a compound that blocked the activity of the JAK enzyme had to be found, often the most difficult part of such a program. The immunology team worked diligently on this and by 2000, seven years after initiating the program, a JAK inhibitor, CP-690,550 (later to be christened tofacitinib) was nominated for clinical development. Before going to humans, tofacitinib was studied at Stanford University in a rigorous monkey model for kidney transplantation. Not only was the compound more effective than the standard of care at the time, cyclosporine, the tofacitinib treated monkeys’ transplanted kidneys had no evidence of tissue injury. The researchers had never seen results like this before.

Studies in humans proved equally exciting. A two week study in patients with severe psoriasis showed that the drug could clear psoriatic plaques almost completely. But the most compelling results were found in rheumatoid arthritis (RA) patients, where tofacitinib was effective in patients in whom the currently used biological drugs were not effective. Pfizer completed clinical trials with tofacitinib in RA and filed a New Drug Application with the FDA late in 2011. Yesterday, the safety and efficacy credentials of tofacitinib were reviewed by the Arthritis Advisory Committee of the FDA and by an 8-2 vote recommended approval of this drug for “the treatment of adult patients with moderately to severely active RA.”

The FDA doesn’t necessarily have to follow the advice of its Advisory Committee but, hopefully, it will, given the severity of this disease and the need for additional options for RA patients. If it is approved, RA patients will be the beneficiaries of the hard work and dedication of the hundreds of Pfizer colleagues who have worked on this program over the last 19 years. But a small degree of thanks should also go to Diane Changelian, who was willing to travel to the woods of Vermont to enable her favorite scientist to attend a conference, and to their son, Haig, who was kind enough not to arrive before his time.